Clinical immunogenicity of biotherapeutics can limit efficacy and contribute to adverse events. Both cellular and humoral immunogenicity can be problematic in a clinical setting. Most often observed in antibodies derived from non-human sources, immunogenicity or the threat thereof has led to extensive protein engineering and platform innovations to mitigate potential immunogenicity. These include humanization, humaneering, veneering, and development of fully human antibody platforms. However, even fully human antibodies and antibody fragments have the risk of being immunogenic. Immunogenicity is often directed toward the CDR regions of an antibody. Conversely, framework region-directed immunogenicity has also been observed, as in the case of single domain antibodies. It has been noted that a significant proportion of people have pre-existing antibodies to the cryptic epitopes within single domain antibodies. Therefore, there exists a need for the generation non-immunogenic single domain antibodies.